<i>FURIN</i> Expression in Vascular Endothelial Cells Is Modulated by a Coronary Artery Disease–Associated Genetic Variant and Influences Monocyte Transendothelial Migration

Abstract

Background Genome-wide association studies have shown an association between the single-nucleotide polymorphism <i>rs17514846</i> on chromosome 15q26.1 and coronary artery disease susceptibility. The underlying biological mechanism is, however, not fully understood. <i>rs17514846</i> is located in the FES Upstream Region (<i>FURIN</i>) gene, which is expressed in vascular endothelial cells (ECs). We investigated whether <i>rs17514846</i> has an influence on <i>FURIN</i> expression in ECs and whether FURIN affects EC behavior. Methods and Results Quantitative reverse transcription-polymerase chain reaction analysis showed that cultured vascular ECs from individuals carrying the coronary artery disease risk allele of <i>rs17514846</i> had higher <i>FURIN</i> expression than cells from noncarriers. In support, luciferase reporter analyses in ECs indicated that the risk allele had higher transcriptional activity than the nonrisk allele. Electrophoretic mobility shift assays using EC nuclear protein extracts detected a DNA-protein complex with allele-specific differential binding of a nuclear protein. Knockdown of FURIN in ECs reduced endothelin-1 secretion, nuclear factor-κB activity, vascular cell adhesion molecule-1, and MCP1 (monocyte chemotactic protein-1) expression and monocyte-endothelial adhesion and transmigration. A population-based study showed an association of the <i>rs17514846</i> risk allele with higher circulating MCP1 levels and greater carotid intima-media thickness. Conclusions The coronary artery disease risk variant at the 15q26.1 locus modulates <i>FURIN</i> expression in vascular ECs. FURIN levels in ECs affect monocyte-endothelial adhesion and migration.